Using existing methods developed in our laboratories, all four stereoisomers of Delta Tyr, Delta Leu and Delta Met will be synthesized and incorporated into the brain peptide, enkephalin. Stabilization to enzymatic degradation and, thus, longer bio-life- times and enhanced bioactivities are expected. NMR + CD spectroscopy will be used to determine the effect of these conformationally constrained amino acid residues on peptide conformation so that a conformation-bioactivity relationship can be developed. C-terminal cyclopropyl Leu and Delta Met will help to elucidate the steric requirements of the various opioid receptors in the brain. We have already synthesized the cyclopropyl Phe4-enkephalins. The sum of the pharmacological results suggest that the four diastereomeric cyclopropyl Phe4-enkephalins offer a rich lead in that the proposed compounds should distinguish actions of alkaloid from peptide opioids and central from peripheral receptors as well. Highly stabilized isomers of the natural enkephalin possessing specific agonist or antagonist activity would be invaluable in clarifying "opioid receptor heterogeneity".